Interstitial Pulmonary Infections
Interstitial infections are a heterogeneous group of chronic inflammation reactions in the lung. There exist different forms of interstitial lung infections, e.g. idiopathic pulmonary fibrosis (IPF), hypersensitive pneumonia or diffused panbronchiolitis. The pathophysiological processes of said diseases are characterised by a combination of tissue injuries and excessive tissue repair processes which leads normal cellular growth to progressive scarring. Said reaction is characterised by repeated destructions of tissue and an intense proteolytic activity with degradation of the structure of extracellular matrix components. Said processes modify the cellular immune response and cause highly induced proliferation of mesenchymal tissue.
Cytokines, such as the tumour necrosis factor alpha, and further growth factors such as the “Transforming growth factor beta1 (TGFbeta 1), have been associated in the art with these processes. TGFbeta appears to be the most important growth factor because it highly stimulates the growth of mesenchymal tissue and because of its capacity to modify cellular immune processes.
TGFbeta is known to cause serious lung fibrosis in animal models in case of increased production thereof. A significantly increased production of said growth factor also appears in cases of human pulmonary fibrosis. It is also known that TGFbeta has immune modifying effect, which includes inhibition of the production of Interferon gamma, suppression of immune reactions correlated to Interferon gamma and induction of immune suppressive CD8+ lymphocytes. Indeed, a modification of the cellular immunity which is not related to the original tissue injury in patients with progressive fibrosises is known for years. More recent researches proved that the progressive scarring in idiopathic pulmonary fibrosis includes modifying the cytokine balance which leads to the reaction called “helper T type 2”. This reaction is characterised by increase of Th2 cytokines, such as interleukin 4 (IL-4), IL-10 and IL-13, as well as by decrease or complete loss of the Interferon gamma production, which is the principle mediator of the reaction called “helper T 1”. In contrast to chronic inflammatory reactions occurring in fibrosis, an acute inflammation of the lung interstitium, e.g. as a result of bacteria infection, is characterised by simultaneous production of cytokines for the production of both type 1 helper T and type 2 helper T, such as the Interferon gamma, IL-12 and IL-4. Additionally, the production of TGFbeta increases, which indication activation of wound healing.
Earlier cellular processes of the disease can hardly be identified due to the fact that idiopathic pulmonary fibrosis is generally diagnosed in an advanced state of disease. The intensity of wound healing is directly influenced by inflammation mechanisms which cause in turn an increased metabolic rate of extracellular matrix components and other cellular components. Chronic inflammations, which are generally caused by infections, cause pathologically excessive wound healing. Even in case of knowing the agents which cause the inflammation, no medical drugs for a successful treatment of organ fibrosis do exist on the market for now. Millions of persons die due to a slow destruction of vital organ systems by a pathological restructuring of the functional tissue. This process is described by the term of fibrosis and is started and regulated by fibroproliferative mechanisms. In our day, the only solution consists in organ transplantation, which means many risks and high costs.
Fibroproliferative reactions affect all organs of the body. Concerning the gas exchange tissue of the lung, they are known under the term of pulmonary fibrosis, in case of affecting the liver, they are called cirrhosis, and in the kidney said reactions are named glomerulosclerosis. All diseases mentioned above can be described as fibroproliferative diseases. In fibrosis, intact tissue is progressively replaced by connective tissue and supporting tissue. This process is based on a pathologically accelerated increase of those tissue cells normally responsible for wound healing. Fibroproliferative diseases are therefore defined diseases with uncontrolled acceleration of wound healing. In fibrosis, the functional organ tissue is replaced until complete loss of the organ function.
Today, more than 150 different mechanisms are known to cause pulmonary injuries, which in turn can cause fibroproliferative wound healing.
Among these mechanisms are chronic infections, exposure to organic and mineral dust, medication and autoimmune mechanisms. The fibriotic process is nonetheless not correlated to said mechanisms. Minor inflammations may result in a dramatic acceleration of the fibrotic process. Chronic virus diseases are probably the most frequent causes of progressive fibrosises, in spite of immunosuppressive treatments. Similar conditions apply to chronic bacteria and fungus infection with or without gastric eructation reaction causing a chronic inflammation of the terminal bronchia which directly influences the chronic wound healing process in the adjacent alveoli. On the cellular scale, the cells presenting antigens such as the dentritic cells play an important role in the pathogenesis of said diseases. They activate in a too intense manner e.g. the T-lymphocytes, which can lead to chronic immune activation. Substances for the treatment of said diseases are therefore needed for inhibiting the excessive activity of dentritic cells.